Cardiac morphogenesis is a complex process that initiates soon after gastrulation as the precardiac mesodermal cells are laid down symmetrically in the forming embryo and subsequently they migrate ventrally to form a linear cardiac tube. Precardiac mesodermal cells will give rise to both, the endothelial and myocardial tissue layers of the straight tube, however, there are discrepancies about whether both cell types share a common progenitor or are derived from separate cell pools. Recently, an emerging concept on heart development has been cast whereby the formation of the developing myocardium is contributed by two distinct cell precursor pools, namely the first and secondary heart fields [1,2]. The first heart field contributes exclusively to the left ventricle, whereas the secondary heart field contributes to the atrial chambers, right ventricle and outflow tract.

Molecular analyses have determined that first heart field precursors are characterized by Nkx2.5 but lack of islet-1 expression [3]. On the contrary, secondary heart field precursors are characterized by co-expressing Nkx2.5 and islet-1 [4]. Retrospective clonal analyses provided further evidences that distinct cell populations are contributing to discrete regions of the developing heart [5,6], in line with those data provided previously.

More recently, a third precardiac population of cells has been inferred, which is characterized by Tbx18 expression but lack of Nkx2.5 and islet-1 expression [7]. These precardiac cells are mainly contributing to the venous pole of the heart.

Two recent papers Ma et al. [8] and Zhou et al [9] have challenged this emerging heart fields concept. Ma et al. [8] describes a set of experiments whereby they report that all cardiac cell layers are derived from Nkx2.5 and islet-1 expressing cells. Zhou et al. [9] describes the proepicardial cells, characterized by Tbx18 expression, are also derived from once expressing Nkx2.5 and islet-1 cells. Thus, these two papers argue in favor of a unifying theory of heart development, in terms of cell precursors, although indeed distinct gene doses and requirements might be needed in distinct cell subsets. Thus, in this context, these studies revealed that all cardiac cells have expressed, at least once, Nkx2.5 and islet-1, including the proepicardial-derived heart-contributing cells. It remains plausible nonetheless that islet-1 expression might be only briefly required within the primary heart-forming cells, whereas it would be compulsory, and at higher levels, in the secondary heart-forming cells. Requirements of Nkx2.5 and islet-1 in the proepicardial-derived cells remain to be explored.

Secondly, the work by Ma et al. [8] nicely demonstrated that Cre-mediated experiments cannot be granted as adequate fate mapping studies. Using the same Cre-deletor line but distinct reporter-LoxP readout lines, the contribution of “tagged” cells to the developing heart, highly differs topologically, but more importantly within distinct cell tissue types. These data are thus highly relevant for the interpretation of Cre/loxP conditional-mediated mouse mutant since deletion of the floxed allele might be in many cases underestimated.